Effects of the interferon-inducer ABPP on colon cancer in rats; importance of tumor load and tumor site

Abstract

ABPP (2-amino-5-bromo-6-phenyl-4-pyrimidinone) is a pyrimidinone with known interferon-inducing, natural killer (NK) cell activity enhancing, antiviral and antitumor properties in several animal species. Its effect on CC531, a dimethylhydrazine-induced, transplantable, weakly immunogenic adenocarcinoma of the colon in WAG rats, was studied. ABPP was found to have no direct cytotoxic effect on CC531 cells in vitro. When small cubes of tumor of equal weight were implanted under the renal capsule, administration of 250 mg/kg of ABPP i.p. on day 0 and +1 led repeatedly to significant (p less than 0.02 up to p less than 0.001) inhibition of tumor growth, when measured on day +7. Lower doses or a single dose of ABPP did not achieve this effect. Late administration (on day +6 and +7) of 250 mg/kg of ABPP in this model was found to have no effect on tumor growth when measured on day +13. When 5 X 10(5) tumor cells were injected in the portal vein, administration of 250 mg/kg of ABPP i.p. on day 0 and +1 reduced significantly (p = 0.002) the number of liver metastases, when counted on day +30. Survival in this group was significantly prolonged (p less than 0.01). However when ABPP was given on day +6 and +7, significantly more (p less than 0.02) metastases in the liver were counted on day +30. The results show a significant antitumor effect of ABPP against tumor CC531 in the subrenal capsule assay (SRCA) model as well as in the liver metastasis model when administered at the time of tumor inoculation. Late administration of ABPP did not inhibit tumor growth in the SRCA and significantly enhanced the development of liver metastases. The role of timing, tumor site, and the mechanisms by which this dual outcome of immunotherapy with ABPP is mediated are discussed. The results of these experiments may have important implications for the design of clinical studies with ABPP.